It’s hard to argue with the findings and conclusions of a new paper in JAMA put forth by Drs. Lydia Pace and Nancy Keating, both physicians with public health degrees and appointments at Harvard-affiliated hospitals. The article, published on April 2, has generated a predictable round of headlines along the lines of “Large Study Finds Little Benefit in Mammography.”

You might, while reading or hearing about this news, wonder about the value of yet another study on breast cancer screening. And you might, if you are following this blog, wonder why I remain convinced that mammography – when done right – has the potential to save many women’s lives and, what’s more, to spare even more from the physical, financial and emotional toll of prolonged treatment for advanced-stage disease.

Why I still think that breast cancer screening is a good idea for most middle-aged women (selected, from a longer list):

1. Several valid studies, most notably that from Sweden, have shown a significant survival benefit of breast cancer screening over the long term. These findings, which demonstrated a benefit to women screened in their forties, received little attention in the news.

2. Mammography is not all the same. It’s not a simple, black-and-white or numeric readout. The “result” depends a lot on the radiologist who interprets the images. Some radiologists, by their training and expertise, deliver lower false positive rates and higher true positive (malignant) “pickup” rates. To say that mammography doesn’t work, based on studies over a population, discounts the potential (and likely) benefit of having the procedure done by experts.

3. Pathology methods have improved over the past three decades. Some doctors, including epidemiologists and PCPs, may not be aware of new tools for evaluating tumors that lessen the risk of over-treating early-stage and indolent tumors.

4. Longer survival is not the only benefit of mammography. Late detection involves risks, and costs. “Screening neglect,” as some researchers call it, adds intensity to needed treatment when patients first seek care for advanced disease. This was the focus of a recent paper in the American Journal of Roentgenology that got little press except for the Cleveland Plains Dealer. The investigators in that careful but retrospective analysis found that among women in their forties, breast cancers detected in routine mammograms were significantly smaller than those detected in women who waited until they felt a lump or had symptoms. That finding was no surprise. But what mattered is that the difference in size of invasive breast cancers found – between screened and unscreened women – translated to less chemotherapy for those screened. The point: finding breast cancer early can reduce the need for toxic and costly treatment.

In reading the new JAMA paper, “A Systematic Assessment…” it seems like the authors are giving a well-prepared talk. Essentially it’s a review of reviews on mammography. Yes, it’s that “meta.” They examined the literature on mammography, going back to 1960 – but with an appropriate emphasis on more recent studies, to address 4 (huge, complex) questions: 1) what is the benefit of mammography screening, and how does it vary by patient age and risk?; 2) what are the harms of mammography screening?; 3) what is known about personalizing screening recommendations? 4) how can patients be supported to make more informed decisions about screening?

This is an ambitious set of questions, to say the least. The tables provided, which are for the most part inconclusive, draw heavily on findings that vary in the era of data collected, methods of analysis, and reasonableness of authors’ assumptions, i.e. validity.

But there is no news on mammography here, except that these two thoughtful investigators carefully reviewed the literature. There are no original data in this ambitious analysis, i.e. there is no new information about mammography’s effectiveness, the false positive rate, the harms of screening, overdiagnosis, etc.

Unfortunately the article, at a glance, may add to the growing perception among journalists, primary care physicians who may not read below the paper’s title, and others – including many ordinary women – that mammography’s effectiveness has been, again, disproved. And so if journalists cover this “story,” as they have and will, our collective memory will incorrectly recall another negative finding, which this is not.

The authors’ main conclusions are that decision aides may be helpful, and that developing better ways of screening for breast cancer would be even better than that. I agree.

It’s a holiday week. But when this morning’s paper delivered yet another op-ed by Dr. H. Gilbert Welch, citing (and breaking an embargo on) yet another, misleading and manipulative two-author analysis of breast cancer screening by him and one other scientist, I thought it worth documenting some concerns.

I’ll start by mentioning that Dr. Welch and I seem to agree on one point – that women should have access to information so they might make reasoned decisions about breast cancer screening. He refers, also, to controversy among professionals about the relative benefits and harms of screening mammography. That there is debate is incontrovertible. No argument there.

The problem is that educated, middle-aged women are being nudged, and frightened, or even charmed into not going for mammography. Nudged, by papers like the one in JAMA today, which acknowledges controversy about statistics and then suggests a falsely low range for lives saved per number of women who get screened. Frightened, by headlines that highlight the risks of overdiagnosis, a statistical concept. If a woman finds out she has an early-stage breast tumor, she and her doctor can (and should) actively decide how much therapy she should have based on the molecular subtype of her tumor, stage and other factors. Just because you find a Stage 0 or small tumor by screening, doesn’t mean you have to over-treat it. If medical education were what it should be, there would be little or no overtreatment because doctors would discuss appropriate options with women and not advise them to have too much therapy. And charmed, yes – by the false notion that breast cancer is often nothing to worry about, that in many cases it can be let alone. That it might just disappear.

I am not aware of a single pathology-documented, published case of a breast tumor going away on its own. Yes, there are slow-growing tumors that may not do harm. But those tend to occur in older women. Those cases are, in general, irrelevant to discussions of breast cancer screening in women between the ages of 40 and 60 or so. What matters most in assessing screening benefits is the number of life-years saved, which is potentially huge for women in this age bracket, and quality of life changes due to the intervention, as assessed over decades.

Mammography (Wikimedia image)

For today, I’ll point to just a few issues in the JAMA paper. The authors state that among 1000 U.S. women age 50 years who are screened annually for a decade, “490 to 670 will have 1 false alarm.” But as detailed in Table 2 of their paper, it turns out the range for women who undergo false-positive biopsies is far lower: between approximately 50 and 100 per thousand women, depending on the age group and study from which the authors draw the “data.” What that means, according to the numbers they’ve culled from studies of non-specialized radiologists, is that only 1 in 10 women would undergo a breast biopsy, and not have cancer, per decade of screening. So the numbers of false positives involving biopsy are not so high.

Most of the false positives are callbacks for additional imaging. Welch and his colleague talk about frequency and anxiety produced by “false alarms.” They go as far as to cite studies documenting that “anxiety may persist for at least 3 years and produce psychological morbidity…” But if women appreciated the data to support that, in most cases – approximately 85 percent – breast cancer can be removed and metastatic disease avoided, over the long haul, by early detection, most of us, and certain anyone making decisions based on reason, wouldn’t mind the follow-up and worrying about irregularities noted on a screening test. Most of us can handle the emotional aspects, and uncertainty, of screening over the course of a few days. To suggest otherwise is patronizing.

Years ago, breast cancer screening was widely considered an act of empowerment, a way for women to take control of their bodies, and to avoid the disfiguring and sadly lethal effects of late-stage breast cancer, besides the potential need for treatment until the end of life. Now, mammography is more accurate and involves less radiation than ever before. Women might be demanding universal access to better, state-of-the-art facilities, rather than shying away from the test.

As for those women who do get called for needle breast biopsies, I say that’s not such an onerous prospect. What’s key is that the procedure be done under local anesthesia, under imaging (typically ultrasound) guidance in an office by a skilled radiologist. The sample should be reviewed by a well-trained breast pathologist, and molecular studies evaluated in a central lab that routinely runs those kinds of tests.

Finally, in the end of today’s op-ed, Welch suggests that the way to reduce uncertainties about breast cancer screening is to carry out costly and somehow randomized clinical trials to see how much and how often screening is needed to demonstrate a survival benefit. But, as his tone suggests, I suspect he doesn’t really favor investment in those clinical trials.

The fact is, I don’t either, at least not for mammography at this point in the U.S. As I and others have pointed out, it takes 15 – 20 years of follow-up in a trial to demonstrate that screening and early detection reduce breast cancer deaths. In North America, the availability of mammography correlates with a reduction in mortality from breast cancer by over a third. He and others have attributed improvements in survival to better treatments. I and others would suggest that while therapy has improved quite a bit since 1985, the greatest benefit derives from most women avoiding the need for life-long treatment by having small tumors found and removed before they’ve spread. This applies in over 80 percent of invasive cases. The survival boost is from the combination, with early detection playing a significant (large) role in the equation.

Why I don’t support starting new randomized trials for mammography, besides that they’d be costly and hard to carry out, is that we can’t wait 20 years to know how best and often to screen women. Rather, it would be better to spend those theoretical research dollars in finding how to prevent the disease. If in 20 years breast cancer is less common, as we all hope will be the case, and true positives are rare, screening of the population won’t be needed. (If breast cancer rates do climb, Bayes’ theorem would support screening, because the positive predictive value of the test would, unfortunately, be higher.) Either way, by 2034 the technology would have improved, or we might have a valid alternative to mammography for screening, and so the studies would be, again, out of date.

It would be better to spend what resources we invest in mammography on improving the quality of screening facilities, now, so that women who decide to go for the procedure can, at least, know that it’s being performed with modern equipment and by doctors and technicians who are capable of state-of-the-art procedures involving the lowest level of radiation exposure possible, careful reading of the images, and application of sonography to further examine the appearance of women with dense breasts, when needed.

This week the USPSTF renewed its position on ovarian cancer screening. The panel reminded the public that there’s no value in doing blood tests, like measuring the CEA, or having sonograms to evaluate healthy-feeling women for the possibility of ovarian cancer. One problem with the CEA measurement is that it goes up in various conditions; it’s not a specific test. Similarly, abdominal ultrasounds tend to pick up all kinds of blobby images that are rarely ovarian tumors. More often than not, ovarian cancer screening tests lead women to undergo more tests, such as CT scans and even surgery, without any benefit. The CEA tests and ultrasounds rarely “catch” ovarian tumors in an early stage.

This information on the lack of effective ovarian cancer screening methods is hardly news. What I hope is that this week’s headlines and editorials don’t add to the blurriness of the public’s perception of cancer screening – that people might think it’s a bad thing all around. The details matter. For some cancers, screening the general population – if it’s done right – can save lives and dollars. That’s because for most tumor types, treating advanced, metastatic disease is costlier than treatment of early-stage, curable tumors.

A few words on other cancers and screening –

Prostate cancer screening by PSA testing has never been shown to save lives. Because prostate cancer is unusual in young men and occurs commonly in elderly men, and in those cases tends to be slow-growing, screening’s potential – even if it were safe and effective – to save men’s life-years is limited. What’s different, also – and I think this is where some journalists get the story wrong by omission – is that early treatment of prostate cancer is rarely beneficial. By contrast, early treatment of breast cancer is often life-saving.

Lung cancer screening may be helpful in people at high risk, such as smoking, but one could argue that the CT scans used in those studies – which involve more radiation exposure than do mammograms, besides that they’re more costly – need a higher threshold of benefit to justify their use.

Colon cancer screening has been shown to save lives. For this tumor type, I think the issue is whether it’s worth doing colonoscopy in everyone over the age of 50, periodically, or better to test everyone for tiny amounts of blood (or, in the future, cancerous DNA markers) in the stool. Checking for occult blood in stood samples is a simple and perfectly safe method of getting a little bit of information about the probability of someone having a polyp or frank malignancy in the gut. If people who want to be screened for colon cancer would reliably take a sampling, it’s possible they might safely skip colonoscopy if there’s no evidence for bleeding or other signs of disease.

As for cervical cancer screening, that has definitely been an advance. Pap smears and other liquid cytology methods, now, perhaps HPV testing, have successfully countered this disease. Years ago, women would present, typically in their 30s, 40s or 50s, with large cancers pushing into the body of the uterus and lower abdomen. These were rarely curable. Rather than a scrape, or slightly bigger procedure in a gynecologist’s office, the women needed hysterectomies and radiation to the pelvis, which caused problems down the road if they were lucky and survived. In communities where young women get gynecological care now, we rarely see advanced cases of cervical cancer. For this disease, the question now is in fine-tuning the frequency of screening and understanding how HPV tests can inform or supplement the Pap smear.

As for mammography in breast cancer screening, please don’t get me wrong. I am not fixed in my position that it’s worthwhile and should be performed every other year in most women over the age of 40 until they reach the age of 70 or so, depending on their wishes and overall health. Rather, I acknowledge it’s far from a perfect screening tool, and I genuinely hope that in the future we’ll prevent breast cancer entirely or at least find a better, safer way to detect it early on. But until that happens, for the time being, mammography is a well-established, routine procedure that is the best we’ve got to prevent tens of thousands of middle-aged women from dying every year in the U.S. from metastatic BC.

I generally ascribe to the “less is more” school of medicine. But that doesn’t mean we should ignore early-stage breast tumors, especially when they occur in young-ish women. Rather, it means that we should treat what cancers we do find carefully and conservatively, with the least therapy needed to raise a woman’s chances of leading a normal, healthy and full life.

Recently I wrote a review of Between the Lines, a helpful handbook on bio-medical statistics authored by an acquaintance and colleague, Dr. Marya Zilberberg. In that post, I mentioned my concern about some of the assumptions and statements on mammography. One thing I liked the book, abstractly, is the author’s efforts to streamline the discussion so that the reader can follow the concepts. But simplification and rounding numbers, “for ease of presentation” (p. 29) can mess up facts, significantly in ways that some primary care doctors and journalists might not appreciate. And so I offer what I hope is a clarification, or at least an extension of my colleague’s work, for purposes of helping women understand the potential benefits and risks of mammography.

In the section on mammography (pp. 28-31), the author rounds down the incidence of breast cancer in women between the ages of 40 and 50 years, from “1 in 70” (1.43%) to “1 in 100” (1%). As any marketing professional might remind us, this small change represents a 30% drop (0.43/1.43) in the rate of breast cancer in women of that age group. This difference – of 30%, or 43%, depending on how you look at it – will factor into any calculation of the false positive (FP) rate and the positive predictive value (PPV) of the test.

For women ages 40-49

Have breast cancer

Don’t have breast cancer

If estimate 1 in 100, 1.0 %

100

9,900

If estimate 1 in 70, 1.43 %

143

9,857

Keep in mind that these same, proportional difference would apply to any BC screening considerations – in terms of the number of women affected, the potential benefits and costs, for the 22,996,493 women between the ages of 40 and 49 counted in the 2010 U.S. Census,

My colleague estimates, fairly for this younger age group of women (who are relatively disposed to fast-growing tumors), that the screening technology (mammography) only picks up 80% of cases; 20% go undetected. In other words – the test is 80% sensitive; the false negative, FN, rate is 20%. In this same section, she considers that the FP rate as 10%. Let’s accept this (unacceptably high) FP rate for now, for the sake of discussion.

As considered in Between the Lines:

If FP rate is 10%, prevalence 1 in 100

Really have BC

Don’t have BC

Total

Mammography +

80

990

1,070

Mammography –

20

8,910

8,930

Total

100

9,900

10,000

But the above numbers aren’t valid, because the disease affects over 1 in 70 women in this age bracket. Here’s the same table with a prevalence of 1 in 70 women with BC:

If FP rate is 10%, prevalence 1 in 70

Really have BC

Don’t have BC

Total

Mammography +

114

986

1,100

Mammography –

29

8,871

8,900

Total

143

9,857

10,000

In this closer approximation to reality, the number of true positives is 114, and false positives 986, among 1,100 abnormal screening results. Now, the PPV of an abnormal mammogram is 114/ (114+986) = 10.4%. So the main statistical point – apart from the particulars of this discussion – is that a seemingly slight rounding down can have a big impact on a test’s calculated and perceived value. By adjusting the BC rate to its prevalence of approximately 1 in 70 women between 40 and 49 years, we’ve raised the PPV from 7.5% to 10.4%.

Here I must admit that I, too, have rounded, although I did so conservatively very slightly. I adopted a 1 in 70 approximation (1.43%) instead of 1 in 69 (1.45%), as indicated on the NCI website. If we repeat the table and figures using a 1 in 69 or 1.45% prevalence rate and 6% FPS, the PPV rises a tad, to 10.5%.

Now, we might insert a different perspective: What if the false positive rate were 6%, as has been observed among sub-specialist radiologists who work mainly in breast cancer screening?

If FP rate is 6%, prevalence 1 in 70

Really have BC

Don’t have BC

Total

Mammography +

114

591

705

Mammography –

29

9266

9,295

Total

143

9,857

10,000

As you can see, if we use a FP rate of 6% in our calculations, the total number of FPs drops to 591 among 10,000 women screened. In this better-case scenario, the PPV of the test would = 114/ (114+591) =16%. Still, that’s not great – and I’d argue that public health officials, insurers and patients should be pushing for FP rates closer to 2 or 3% – but that’s irrelevant to my colleague’s point and her generally instructive work.

My second concern has to do with language, and making the consequences of false positives seem worse than they really are. On page 29, the author writes: “ So, going back to the 10,000 women being screened, of 9,900 who do NOT have cancer… 10%, or 990 individuals will still be diagnosed as having cancer.” The fact is, the overwhelming majority of women with positive mammograms won’t receive a cancer diagnosis. Rather, they’ll be told they have “an abnormal result, or a finding that suggests the possibility of cancer and needs further evaluation,” or something along those lines. It would be unusual in practice to jump from a positive mammogram straight to a breast cancer diagnosis. There are steps between, and every patient and journalist should be aware of those.

—
Finally, if I were to write what I really think, apart from and beyond Between the Lines – I’d suggest the FP rate should be no higher than 2 or 3% in 2012. This is entirely feasible using extant technology, if we were to change just two aspects of mammography practice in the U.S. First, require that all mammograms be performed by breast radiologists who get extra training and focus in their daily work almost exclusively on breast imaging. Second, make sonograms – which, together with mammograms, enhance the specificity of BC screening in women with dense breasts– universally available to supplement the radiologists’ evaluations of abnormal mammograms and dense breasts in younger women.

By implementing these two changes, essentially supporting the practice of sub-specialists in breast radiology, we could significantly lower the FP rate in breast cancer screening. The “costs” of those remaining FPs could be minimized by judicious use of sonograms, needle biopsies and other measures to reduce unnecessary surgery and over-treatment. Over the long haul, we need to educate doctors not to over-treat early stage disease, but that goes far beyond this post and any one woman’s analysis of mammography’s effectiveness.

2. The researchers use mathematical arguments so complex to prove a point that Einstein would certainly, 100%, without a doubt, take issue with their model and proof.

3. “Overdiagnosis” is not defined in any clinical sense (such as the finding of a tumor in a woman that’s benign and doesn’t need treatment). Here, from the paper’s abstract:

The percentage of overdiagnosis was calculated by accounting for the expected decrease in incidence following cessation of screening after age 69 years (approach 1) and by comparing incidence in the current screening group with incidence among women 2 and 5 years older in the historical screening groups, accounting for average lead time (approach 2).

No joke: this is how “overdiagnosis” – the primary outcome of the study, is explained. After reading the paper in its entirety three times, I cannot find any better definition of overdiagnosis within the full text. Based on these manipulations, the researchers “find” an estimated rate of overdiagnosis attributable to mammography between 18 -25% by one method (model/approach 1) or 15-20% (model/approach 2).

4. The study includes a significant cohort of women between the ages of 70-79. Indolent tumors are more common in older women who, also, are more likely to die of other causes by virtue of their age. The analysis does not include women younger than 50 in its constructs.

5. My biggest concern is how this paper was broadcast – which, firstly, was too much.

Bloomberg News takes away this simple message in a headline: “Breast Cancer Screening May Overdiagnose by Up to 25%.” Or, from the Boston Globe’s Daily Dose, “Mammograms may overdiagnose up to 1 in 4 breast cancers, Harvard study finds.” (Did they all get the same memo?)

The Washington Post’s Checkup offers some details: “Through complicated calculations, the researchers determined that between 15 percent and 25 percent of those diagnoses fell into the category of overdiagnosis — the detection of tumors that would have done no harm had they gone undetected.” But then the Post blows it with this commentary, a few paragraphs down:

The problem is that nobody yet knows how to predict which cancers can be left untreated and which will prove fatal if untreated. So for now the only viable approach is to regard all breast cancers as potentially fatal and treat them with surgery, radiation, chemotherapy or a combination of approaches, none of them pleasant options…

This is simply not true. Any pathologist or oncologist or breast cancer surgeon worth his or her education could tell you that not all breast cancers are the same. There’s a spectrum of disease. Some cases warrant more treatment than others, and some merit distinct forms of treatment, like Herceptin, or estrogen modulators, surgery alone…Very few forms of invasive breast cancer warrant no treatment unless the patient is so old that she is likely to die first of another condition, or the patient prefers to die of the disease. When and if they do arise, slow-growing subtypes should be evident to any well-trained, modern pathologist.

“Mammograms Spot Cancers That May Not Be Dangerous,” said WebMD, yesterday. This is feel-good news, and largely wishful.

A dangerous message, IMO.

—

Addendum, 4/15/12: The abstract of the Annals paper includes a definition of “overdiagnosis” that is absent in the body of the report: “…defined as the percentage of cases of cancer that would not have become clinically apparent in a woman’s lifetime without screening…” I acknowledge this is helpful, in understanding the study’s purpose. But this explanation does not clarify the study’s findings, which are abstract. The paper does not count or otherwise directly measure any clinical cases in which women’s tumors either didn’t grow or waned. It’s just a calculation. – ES

Last week the Annals of Internal Medicine published a new report on how doctors (don’t) understand cancer screening stats. This unusual paper reveals that some primary care physicians – a majority of those who completed a survey – don’t really get the numbers on cancer incidence, 5-year survival and mortality.

The report shows, plainly and painfully, that too many doctors are confused and even ignorant of some statistical concepts. Nothing more, nothing less. The new findings have no bearing on whether or not cancer screening is cost-effective or life-saving.

What the study does suggest is that med school math requirements should be upped and rigorous, counter to the trend. And that we should do a better job educating students and reminding doctors about relevant concepts including lead-time bias, overdiagnosis and – as highlighted in two valuable blogs just yesterday, NPR Shots and Reporting on Health Antidote – the Number Needed to Treat, or NNT.

The Annals paper has yielded at least two unfortunate outcomes. One, which there’s no way to get around, is the clear admission of doctors’ confusion. In the long term, this may be a good thing, like admitting a medical error and then having QA improve as a consequence. But meanwhile some doctors at their office desks and lecterns don’t realize what they don’t know, and there’s no clear remedy in sight.

Dr. Moyer, in her editorial, writes that medical journal editors should carefully monitor reports to ensure that results aren’t likely misinterpreted. She says, in just one half-sentence, that medical educators should improve teaching on this topic. And then she directs the task of stats-ed to media and journalists, who, she advises, might follow the lead of the “watchdog” HealthNewsReview. I don’t see that as a solution, although I agree that journalists should know as much as possible about statistics and limits of data about which they report.

We lie, we cheat, we steal, we are confused… What else can doctors do wrong?

The second, and I think unnecessary, problematic outcome of this report is that it’s been used to argue against cancer screening. In the editorial Dr. Moyer indulges an ill-supported statement:

…several analyses have demonstrated that the vast majority of women with screen-detected breast cancer have not had their lives saved by screening, but rather have been diagnosed early with no change in outcome or have been overdiagnosed.

The problem of overdiagnosis, which comes up a lot in the paper, is over-emphasized, at least as it relates to breast cancer, colon cancer and some other tumors. I have never seen a case of vanishing invasive breast cancer. In younger women, low-grade invasive tumors are relatively rare. So overdiagnosis isn’t applicable in BC, at least for women who are not elderly.

In the second paragraph Dr. Moyer outlines, in an unusual mode for the Annals, a cabal-like screening lobby:

…powerful nonmedical forces may also lead to enthusiasm for screening, including financial interests from companies that make tests or testing equipment or sell products to treat the conditions diagnosed and more subtle financial pressures from the clinicians whose daily work is to diagnose or treat a condition. If fewer people are diagnosed with a disease, advocacy groups stand to lose contributions and academics who study the disease may lose funding. Politicians may wish to appear responsive to powerful special interests…

While she may be right, that there are some influential and self-serving interests and corporations who push aggressively, and maybe too aggressively for cancer screening, it may also be that some forms of cancer screening are indeed life-saving tools that should be valued by our society. I think, also, that she goes too far in insinuating that major advocacy groups push for screening because they stand to lose funding.

I’ve met many cancer agency workers, some founders, some full-time, paid and volunteer helpers – with varied priorities and goals – and I honestly believe that each and every one of those individuals hopes that the problem of cancer killing so many non-elderly individuals in our society will go away. It’s beyond reason to suggest there’s a hidden agenda at any of the major cancer agencies to “keep cancer going.” There are plenty of other worthy causes to which they might give their time and other resources, like education, to name one.

Which leads me back to the original paper, on doctors’ limited knowledge –

As I read the original paper the first time, I considered what would happen if you tested 412 practicing primary care physicians about hepatitis C screening, strains, and whether or not there’s a benefit to early detection and treatment of that common and sometimes pathologic virus, or about the use of aspirin in adults with high blood pressure and other risk factors for heart disease, or about the risks and benefits of drugs that lower cholesterol.

It seems highly unlikely that physicians’ uncertainty is limited to conceptual aspects of cancer screening stats. Knowing that, you’d have to wonder why the authors did this research, and why the editorial pushes so hard the message of over-screening.

Last week the NEJM published two major papers on screening for colon and rectal cancer. The most notable finding supports that colonoscopy – when done properly and not necessarily often – saves lives.

The NCI estimates that doctors will find over 103,000 colon and 40,000 rectal cancers, and the number of deaths will exceed 51,000 this year in the U.S. According to the ACS, colorectal cancer ranks third as a cause of cancer mortality in men and in women. In light of these numbers, the potential for screening to reduce deaths and costs of treating people with advanced disease is great.

Both analyses are unfortunately – almost dauntingly – complicated. An accompanying editorial, by Drs. M. Bretthauer and M. Kalager lends some perspective.

colon adenoma pathology, H&E stain, (Wiki Commons: "Nephron")

The first report comes from a group of researchers led by Ann Zauber, PhD, a biostatistician at MSKCC. This team examined long-term outcomes among 2602 adults who had adenomatous polyps removed between 1980 and 1990, followed by colonoscopy recommended at varying intervals in a trial. With a median follow-up of 15.8 years, there were only 12 deaths from colon cancer in the study population – essentially half the number expected by comparison with SEER data.

The main limitations I see in this report are two. First, what might be considered a good thing – the high compliance rate: 81% of those with adenomas underwent some follow-up colonoscopy. And second – along a similar vein – that the colonoscopies were performed by highly-trained physicians at academic centers in a trial that mandated a certain degree of thoroughness and quality. Some criticism of the work is that the findings won’t translate to the community at large, as mentioned in the editorial and in the paper itself. That’s because some “real world” gastroenterologists don’t perform the procedure so carefully. Apart from the trial, many people are genuinely hesitant about having colonoscopy out of concern about its unpleasantness and also costs. Compliance with colonoscopy recommendations runs low.

These are valid concerns. But they don’t abrogate the value of the procedure. Rather, they point to the need for rigorous training of doctors who do colonoscopy, for close monitoring of facilities where it’s done (and in path labs, where the specimens are evaluated), and for insurance or a national health plan to enable patients, if they choose, to have this potentially life-saving screening test covered.

The second study, from a group in Spain, examined the relative merits of checking stool samples for blood every two years vs. colonoscopy every ten years in over 50,000 people. The preliminary finding – after just one “round” of colonoscopy in those assigned to that trial arm, is that a higher proportion complied with fecal blood testing than with colonoscopy. Among those who underwent colonoscopy, cancers and adenomas were found in a greater fraction. But the absolute number of cancers detected was essentially the same in each group, because more people assigned to fecal screening completed the task.

My take from these reports, combined, is that periodic colonoscopy has the potential to halve the number of deaths from colon cancer in the general population. But it’s an unpleasant, invasive and expensive test that does carry some risks. The quality of the test – both in terms of its thoroughness and risk of complication – would depend, in part, on the training and experience of the doctor who performs the test. So, as with mammography, I favor heavy regulation and careful certification of physicians who perform these procedures.

As to how colonoscopy relates to fecal blood testing as a screening method at the population level, and the optimal start and frequency of either test, those remain uncertain. Dr. Zauber, it turns out, heads the NCI-funded National Colonoscopy Study. This ongoing work will, hopefully, shed light on how testing for blood in stool samples compares with colonoscopy in colon cancer screening and, ultimately, costs and mortality from late-stage disease.

1. Conventional cytology (as in a Pap smear; the cervix is scraped and cells splayed onto a microscope slide for examination);

2. Liquid-based cytology (for LBC, the NHS explains: the sample is taken as for a Pap test, but the tip of the collection spatula is inserted into fluid rather than applied to slides. The fluid is sent to the path lab for analysis);

These HPV assays use distinct methods to assess DNA of various HPV strains.

There’s a lot of jargon here, and I have to admit some of this was new to me despite my nearly-due diligence as a patient at the gynecologist’s office and my familiarity as an oncologist with the staging, clinical manifestations and treatment of cervical cancer. Who knew so many decisions were made during a routine pelvic exam about which manner of screening?

2. It seems that at some medical centers, and possibly overall, there’s a lower proportion of inadequate cell specimens when practitioners skip the slides and use the liquid method. This means that fewer women need be called back for another procedure.

3. Finding HPV sequences in the cervix yields many false positives, in terms of malignancy.

The researchers conclude that further studies are needed to sort out how HPV testing can improve or supplement cervical cancer screening. The main limitation is that many young women are infected with potentially cancer-causing strains of HPV, but most don’t get cervical cancer. When cervical cancer does develop that’s usually later on, a decade or longer after the relevant viral infection.

The second Annals article, a helpful narrative review, considers the practical implications of the above findings. The authors state that over 40 types of HPV can infect the cervix. They review that progression to cancer occurs along these 4 steps: HPV transmission, acute infection, persistent infection causing precancerous changes and eventually, in a subset of those infected, invasive cervical cancer.

Figure 1 is remarkably clear:

Prevalence of high-risk HPV and incident cases of cervical cancer in the U.S., 2003–2005. Surveillance Epidemiology and End Results (SEER) data for incident cases among females aged 15 to 19 years and 50 to 64 years.

The graph shows that the prevalence of HPV infection is highest among teens and women in their early 20s, and decreases in older women. By contrast, the incidence of cervical cancer rises steadily in women over 30 years and remains elevated among women in their 40s. The authors show, separately, that the rate of cervical cancer in older women is low.

The central point is that high-risk HPV infection and associated inflammation of the cervix are common in young women, but cervical cancer is rare among those under 30 years. The investigators conclude that cervical cancer screening in women younger than 20 years may be harmful. They also state that evidence supports discontinuation of cervical cancer screening in most women who are over 65 years old.

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Two asides on this otherwise non-bloggy topic –

It’s great that the Annals provides the full text of these papers open-access, free of charge to the public.

Amazing how well-accepted is the concept of some viruses causing cancer, today. This was a heretical idea 25 years ago in academic medicine; now it’s dogma.

I’m wondering is how to bring mainstream health journalists and women who are, lately, choosing not to have mammograms, to their senses about a persuasive but flawed argument put forth by a Dartmouth epidemiologist and others in a crew of seemingly like-minded, hopefully well-intentioned, some perhaps tenure-seeking and others grant-needing, circulatory bias-confirming academics who meet and discuss and write about the so-called dangers of mammography.

Maybe some doctors and journalists think they’re doing the right thing by informing a naïve body of women who, in the words of an LA Times writer today, think only correlative and simple thoughts.

If you or someone you know discovered she had breast cancer thanks to routine mammography screening, and if you or that friend with breast cancer got treatment and today is cancer-free, it’s natural to assume that the mammogram was a life-saver.

But odds are, it wasn’t….

First things first: the title makes an assumption about what I, or you, or any reader, thinks.

Second, the story offers two factoids: first – that over 75% of women diagnosed with BC by screening mammography wouldn’t have died from the cancer if they hadn’t had mammography; and second – that no more than 25% of those same women can rightly credit a mammogram for saving their lives. But this is just one stat, or falsehood, based on the true, assumption-free relationship between 75% and 25%.

Dr. H. Gilbert Welch, who recently likened mammography-taking to gambling, plays freely with impressive-sounding information sources. He and his coauthor used data from the NCI. Seemingly hard to argue with those kinds of numbers. But they used old data, again, and employ numerous assumptions (what the authors call generous, but I wouldn’t) to render calculations and “prove” their point published in the Archives of Internal Medicine.

“…We created a simple method to estimate the probability that a woman with screen-detected breast cancer has had her life saved…

Simple? Don’t you believe it.

There’s a Wellpost in the New York Times today covering the same Archives of Internal Medicine article. Not surprisingly, this draws positive feedback in the comments and Twitter-chatter. Some of the more understandable discussion comes from women with metastatic disease whose tumors were missed by screening mammography. Notably, neither paper quotes an oncologist.

Here in the U.S. where we do spend too much on health care, we all know women whose breast tumors were missed by screening mammograms. This happens, and it’s awful, but it doesn’t and certainly shouldn’t happen so often as some doctors seem to think. Extrapolating from personal observations to draw conclusions about a procedure’s value is flawed reasoning, either way.

I agree with many of Dr. Susan Love’s school, and most of the NBCC agenda, and others that say breast cancer prevention would be better than treatment. How could I not?

But until there’s a prevention for BC, which I’m sorry to report is unlikely to happen before 2020, especially because it’s really 15 or 20 or maybe even more diseases that would, presumably, need distinct methods of prevention, and until there are better, less damaging and less costly remedies, mammography may be the best way for middle-aged women to avoid the debilitating and lethal effects of late-stage disease. And for society to avoid the costs of that condition and its treatments, which are huge.

Days ago, the USPSTF issued a new draft for its recommendations on routine PSA measurements in asymptomatic men. The panel’s report is published in the Annals of Internal Medicine. The main findings are two: first, the absence of evidence that routine PSA testing prolongs men’s lives, and second, that PSA evaluation may, on balance, cause more harm than good.

Not surprisingly, there’s been considerable coverage of this by the media, and some controversy. For decades, many men have had their PSA checked, knowingly or not, by their physicians. The PSA test measures the level of Prostate Specific Antigen, a protein produced and sometimes secreted by prostate cells, normal, inflamed or malignant, into the bloodstream.

As an oncologist, I don’t find the panel’s recommendations surprising. There’s never been strong data to support the hypothesis that routine PSA testing reduces mortality for men in any age group. Prostate cancer is often indolent, a slow-growing kind of tumor for which a “watch and wait” approach may be best, especially when it occurs in elderly men who are most likely, even in the absence of treatment, to die of another cause. The complication rate of prostate surgery is fairly high, although this “cost” of screening likely varies, depending on the skill of the surgeon. Still, and understandably, there are men who swear by this measurement, whose lives have been, in some cases, saved by early detection of a high-grade tumor upon screening.

For today, I’d like to consider some key differences between breast and prostate cancers, and the potential value of screening:

Based on SEER data, the median age of a breast cancer diagnosis in the U.S. is 61 years. The median age of death from breast cancer is 68 years. For prostate cancer, the SEER data show a median age of 67 years at diagnosis, and for death from prostate cancer, 80 years.

So the potential number of life-years saved by early detection and intervention is, on average, greater for breast cancer than for prostate cancer.

2. Screening for breast cancer has improved over the past 25 years.

Because the blood test for PSA hasn’t changed much in decades, it’s reasonable to consider studies and long-term survival curves based on data going back to the 1980s.

Mammography, by contrast, is much safer and better than it was 25 years ago, for various reasons: increased regulation of mammography facilities (more care with the procedure, better training and credentialing of technicians) according to the FDA’s Mammography Quality Standard Acts Program ; development of ultrasound methods to supplement mammograms in case of suspicious lesions (lessens the false positive rate overall); the advent of digital technology (lessens the false positive rate in younger women and others with dense breasts); more breast radiology specialists (expertise).

The data reviewed by the USPSTF in issuing their 2009 recommendations for BC screening were decades old, and, as I’ve considered previously, irrelevant to modern medical practices. A recent article in the NEJM points to the problem of the panel’s reliance on the Age trial for women in their 40s. That trial involved the obsolete method of single-view mammography.

A woman knows if she’s getting a mammogram. She may not ask sufficient questions of her doctor, or her doctor may not answer them well, but in the end she does or doesn’t enter into a radiology room, volitionally. She decides to get screened, or not. She can choose to have a mammogram every year, or every other year, or not at all.

This perspective might, and should, later extend to consider additional differences between these two kinds of malignancies (each of which is really a group of cancer subtypes), a fuller discussion of the impact of treatment on survival for each type, and the relative risks of screening due to differential complication rates of biopsies and other procedures.

To be clear, there’s no perfect screening test for either cancer type. Far from it. But the merits and risks of each procedure should be weighed separately, and with care.